Advancing Cancer Therapy with Copper/Disulfiram Nanomedicines and Drug Delivery Systems

Abstract

Disulfiram (DSF) is a thiocarbamate based drug that has been approved for treating alcoholism for over 60 years. Preclinical studies have shown that DSF has anticancer efficacy, and its supplementation with copper (CuII) significantly potentiates the efficacy of DSF. However, the results of clinical trials have not yielded promising results. The elucidation of the anticancer mechanisms of DSF/Cu (II) will be beneficial in repurposing DSF as a new treatment for certain types of cancer. DSF's anticancer mechanism is primarily due to its generating reactive oxygen species, inhibiting aldehyde dehydrogenase (ALDH) activity inhibition, and decreasing the levels of transcriptional proteins. DSF also shows inhibitory effects in cancer cell proliferation, the self-renewal of cancer stem cells (CSCs), angiogenesis, drug resistance, and suppresses cancer cell metastasis. This review also discusses current drug delivery strategies for DSF alone diethyldithocarbamate (DDC), Cu (II) and DSF/Cu (II), and the efficacious component Diethyldithiocarbamate-copper complex (CuET).

Keywords: cancer; cuproptosis; disulfiram/copper; drug delivery systems; immunomodulatory effects; nanomedicines.

Figure 3

Cancer cells have unlimited proliferative capacity, and DSF/Cu (II) has been shown anti-proliferation effects towards cancer cells. (a) DSF/Cu (II) inhibits cancer cell proliferation, preventing the transformation of small cancer lesions to large tumors. Created with BioRender.com accessed on 8 May 2023 (b). Angiogenesis is an essential step for cancer metastasis; the VEGF in the cancer microenvironments contributes the massive and abnormal vessels in cancer lesions, and DSF/Cu (II) inhibits the angiogenesis behavior and prevents cancer metastasis to lung and bone, etc., sites. Created with BioRender.com. accessed on 8 May 2023 (c) Cancer stem cells aggravate the angiogenesis and drug resistance of cancer; DSF/Cu (II) inhibits cancer stem cells and thus shown potency in anti-angiogenesis and anti-drug resistance. Created with BioRender.com accessed on 8 May 2023 (d). Drug resistance is a typical phenomenon during the treatment of cancer; novel copper diethyldithiocarbamate nanoparticles can effectively overcome drug-resistant cancers, owing to being non-binding to P-gp and being maintained in the cancer cells. Copyright 2023, Elsevier [141].

Figure 1

The chelation mechanism of DSF and Cu (II) and the use of DSF-based therapy for different types of cancer. DSF metabolizes to diethyldithiocarbamate (DDC or ET) via the glutathione reductase system; the active anti-cancer ingredient DDC further chelates with Cu (II) and forms Cu(DDC)₂ (aka CuET), which has anti-cancer efficacy. The high dose of DSF alone and low dose of DSF/Cu (II) are effective in various cancers including liver, ovarian, prostate, breast, lung cancer, and glioblastoma (GBM). Created with BioRender.com. accessed on 19 April 2023.

Figure 2

The summary of roles of DSF/Cu (II) in cancer microenvironment. Left: DSF/Cu (II) inhibits the cancer proteasome activity via p97-NPL4 pathway; in addition, DSF/Cu (II) inhibits cancer-associated ALDH activity and inhibits cancer stem cells (CSCs). In the cancer microenvironment, aberrant enzyme activity, superoxide dismutase 1 (SOD1) and catalase (CAT), results in the elevation of ROS; the higher basal level of ROS benefits cancer proliferation. However, the further increased ROS to exceed cancer tolerance cause cancer death. Right, the DSF/Cu (II) reprograms the tumor-promoting macrophage M2 to anti-tumor type M1. In addition, DSF/Cu (II) transforms the immune-suppressive (cold) tumor microenvironment to the immune-active (hot) microenvironment via the induction of immunogenic cell death (ICD). Created with BioRender.com. accessed on 19 April 2023.

Figure 4

Divergent nanotechnology and chemical modulation-based formulations to enhance DSF anticancer effects. To sum up, DSF-based nanomedicine includes DSF alone, DDC prodrug delivery system, delivery system for Cu (II) and DSF/Cu (II), and drug delivery system for active component-CuET.

Figure 5

Typical examples of the DSF delivery system and DDC prodrug: (a) DSF-loaded pH-triggered PEG-shedding TAT peptide-modified lipid nano capsules [160]. Copyright 2015, American Chemical Society. (b) Near-infrared light triggered activation of pro-drug combination cancer therapy and induction of immunogenic cell death, (1) NIR laser + CuS NP treatment increases intracellular ROS. (2) ROS converts DQ prodrug to DDC. (3) CuS NP release Cu (II). (4) DDC and Cu (II) form Cu(DDC)₂ active anticancer complex. (5) Cu(DDC)₂ chemotherapy and ROS induce immunogenic cell death in cancer cells [101]. Copyright 2015 © 2021 Elsevier B.V.

Figure 6

(a) Schematic illustration: The DSF@PEG/Cu-HMSNs nano system triggers tumor-specific DTC-Cu (II)chelation (pathway I to II) and Cu+-initiated Fenton-like reaction (pathway I to III). This enhances the antitumor efficacy of DSF-based chemotherapy without systemic toxicity. Copyright 2019, American Chemical Society [174]. (b) Schematic illustration of albumin-based dual-targeting biomimetic delivery of Rego and DSF/Cu for cancer therapy. Copyright 2021, Wiley-VCH [192].

Figure 7

Schematic comparison of (a) film-dispersion method (Created with BioRender.com) accessed on 8 May 2023 vs. (b) stabilized metal ion ligand complex (SMILE) technology [25]. Copyright © 2018 American Chemical Society. (c) Drug loading efficiency of film-dispersion method and stabilized metal ion ligand complex (SMILE) technology [25]. Copyright © 2018 American Chemical Society. (d) The scale of SMILE technology using a 3D-printed microfluidic device [32]. Copyright © 2019 Elsevier Ltd.

Figure 8

The pros and cons of the different delivery strategies.